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Does metastasis happen earlier than previously thought?


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Sharon Begley discusses an unconventional new idea about how cancer cells spread (a process known as metastasis) in her recent piece for the website STAT. She states that, “cancer cells spread way earlier than thought, seeding metastases that cause most deaths.” (3/28/17)


How scientists believe cancers spread

For years, cancer biology students were taught that tumors initially form in the original organ or tissue (called a primary tumor), and can then spread (metastasize) to a distant organ. Typically, the primary tumor is thought to be detectable, whether it is found as a lump that can be felt by a person or health care provider or as a mass on a mammogram or other imaging technology.

Metastasis is thought to be a very late event in cancer progression. As the primary tumor grows, the cells acquire genetic changes called mutations. Some of these genetic changes are believed to help a few cells break free of the primary tumor and spread to another organ—some ER+ breast cancers, for example, develop the ability to spread to the bone. In this line of thinking, cancer cells that metastasize are thought to be more mutated forms of the cells that make up the primary tumor.

But what if this traditional hypothesis about how cancer spreads is not completely correct, and metastatic cancers can form early in cancer development?

What if some of the cells that can metastasize do not migrate from a primary tumor that is detectable from a lump or imaging such as a mammogram? What if metastatic cancer occurs earlier in cancer development than previously thought, originating from a cell that migrates away from the breast before the primary tumor fully forms.

Today, health care providers use information from a primary tumor’s genetic sequence to help select cancer treatments for patients that hopefully remove all cancer cells so that metastasis does not occur later. This genetic information, however, is acquired later rather than sooner during cancer development. If metastatic cancer can develop early in cancer progression, current prescribed treatments may not be as useful against early cancer cells, which do not have the same genetic information as more mature cancer cells.

Mutations in the cells of both early and late metastatic cancer most likely differ from the primary tumor. But it is important for researchers to learn more about early metastasizing cancer cells, which may not have as many mutations as cells from cancers that have been growing for a longer period of time, and therefore may require different treatment strategies. More research is needed to understand whether these early cells are good targets for therapy and how they can be used if they are.

Understanding how metastasis occurs and when the first cells migrate away from the primary tumor is critical for developing treatments for metastatic cancers

In a recent STAT article, journalist Sharon Begley examines two independent research studies published in the December 2016 issue of Nature by Kathryn Harper (Icahn School of Medicine at Mount Sinai), and Hedayatollah Hosseini (University of Regensburg) and colleagues from various institutions that considered this unconventional theory of metastatic cancer in mice with HER2+ breast cancer, one of the breast cancer subtypes found in humans.

These two studies found that not only can cancer cells spread in mice earlier than previously thought—before the primary tumor is detectable—but these early spreading cells form metastases more efficiently than cancer cells that spread later in cancer development.

Research is still in the early stages

While these findings are interesting and may change how researchers and health care providers think about how cancer spreads, it is important to remember that they are preliminary findings from laboratory studies of mice. While early studies such as these are crucial for helping to identify disease mechanisms, what happens in mice does not necessarily correlate to what happens in humans.

In commentary that accompanied the research papers, Dr. Cyrus Chajar of the Fred Hutchinson Cancer Research Center and Dr. Mina Bissell of the Lawrence Berkeley National Laboratory noted that this research was limited to HER2+ breast cancer, and that it is possible that the mechanism of metastasis uncovered by this research may not apply to other cancers or even to other subtypes of breast cancer.  Still, Drs. Chajar and Bissel state that these studies have major implications regarding preventative therapies, and that researchers should further understand and “aim to target the characteristic properties” of early metastasis-forming cancer cells.

What do these results mean for me?

Clearly, much more work needs to be done in the laboratory to confirm these findings and find ways to apply them to the treatment of human cancers. In the meantime, patients who have had a primary tumor should follow the treatment and screening regimen recommended by their oncologists and be alert to signs of metastasis. And while symptoms of metastatic breast cancer do not always occur, the National Cancer Institute recommends that patients who have had a primary cancer should talk to a health care provider if they experience any of the following:

  • Pain and fractures, which may indicate spread to the bone
  • Headache, seizures, or dizziness, which may indicate spread to the brain
  • Shortness of breath, which may indicate spread to the lung
  • Jaundice or swelling in the belly, which may indicate spread to the liver

Questions to Ask Your Health Care Provider

  • What signs and symptoms should I look for if I am concerned that my cancer has spread?
  • I have metastatic breast cancer, have both my primary tumor and my metastatic tumor been sequenced?

Posted 3/28/17

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References:

Bergley S. “Cancer cells spread way earlier than thought, seeding metastases that cause most deaths.” STAT. Published online on December 14, 2016. 

Ghajar CM and Bissell MJ. “Metastasis: pathways of parallel progression.” Nature. 540, 528-529 (published online 22 December 2016). 

Harper KL, Sosa MS, Entenberg D, et al. “Mechanism of early dissemination and metastasis in Her2+ mammary cancer.” Nature. 540: 588-92 (published online 22 December 2016). 

Hosseini H, Obradovic M, Hoffmann M, et al. “Early dissemination seeds metastasis in breast cancer.” Nature. 540: 552-558 (published online 22 December 2016). 

NIH: National Cancer Institute. “Metastatic Cancer.” 

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